Pancreatic cancer is a highly lethal malignancy with an extremely poor prognosis. A wide variety of biochemical and genetic aberrations have been identified to be associated with the pancreatic cancer. MUC4, encoding for a transmembrane mucin protein, is among the most differentially-expressed genes in pancreatic adenocarcinoma with no detectable expression in the normal pancreas. It is overexpressed in a significant number of pancreatic carcinomas, and its neoexpression is observed early in pancreatic tumor development i.e., in precancerous lesions. MUC4 has been shown to interact with and stabilize the expression of HER2 oncoprotein and contains structural motifs that can putatively interact with extracellular matrix, membrane and cytoplasmic proteins. MUC4 potentiates tumor growth and metastasis of pancreatic cancer cells and a recent study have shown that it is an independent factor for poor prognosis. All these studies underscore the importance of identifying the molecular mechanisms involved in the aberrant expression of MUC4, so that, it can be exploited clinically for therapeutic purposes. A new class of gene regulatory RNAs, termed as microRNAs (miRNAs) has gained significant interest for their ability to influence various biological process. A large number of miRNAs has been identified in humans. Nevertheless, the target mRNAs have been assigned to only a few of them. The hypothesis of this proposal is that the aberrant expression of a certain class of microRNAs in pancreatic cancer is responsible for MUC4 dysregulation and is implicated in the malignant progression of pancreatic cancer cells. This proposal will initiate efforts in three specific aims on investigating the expression profile of candidate MUC4-targeted miRNAs in pancreatic cancer (Aim 1), studying their role in MUC4 regulation (Aim 2), and characterize their effect on pancreatic cancer phenotype (Aim 3). Taken together, the proposed studies will unfold a novel regulatory mechanism for MUC4 expression in pancreatic cancer cells and ascribe the functional significance to the MUC4-targeted miRNAs in pancreatic cancer progression. The information gained from these studies will be vital in supporting the design of miRNA-based therapeutic strategies and clinical assays in pancreatic cancer. PUBLIC HEALTH RELEVANCE: The proposal will investigate the expression and functional significance of the candidate MUC4-targeted miRNAs in pancreatic cancer and may provide important information to support the design of miRNA-based therapeutic strategies and clinical assays for pancreatic cancer.